IntrOductIOn
Cancer is one among the leading causes of morbidity and mortality
worldwide. In 2014-15, 14.1 million new cases of cancer were
diagnosed 7.4 million (53%) in male and 6.7 million (47%) females.
Nearly eight lac cancer cases are prevalent in India at any point
of time and 5,50,000 cancer patients dying every year [1]. Despite
thumping advances in cancer therapeutics, from conventional
non-targeted therapy to non-targeted therapy, availability of monoclonal
antibodies, immunotherapy and so on, prognosis of cancer in many
cases remains unaltered. The main reasons from therapeutics
point of view are resistance to cancer drugs and regional spread of
disease. Resistance to cancer drugs is a major threat that leads to
failure of treatment recurrence of disease among treated population.
Metronomic chemotherapy appears to be prowess to address the
resistance and regional spread of cancer by many ways [2].
The Scientist, Doughlas Hanahan coined the term ‘metronomic
chemotherapy’. The basic principles involved behind such
chemotherapy regimen are administering anti-cancer drugs in low
doses continuously or at regular intervals but more often than the
cyclical conventional anti-cancer therapy schedules.
At present, many experimental works are being carried to explore
functional mechanisms of metronomic chemotherapy while on
the other side of coin, cancer trials comparing conventional and
metronomic regimen are progressing [3].
Our specific objectives were focused to provide comprehensive data
of trials employing metronomic chemotherapy, pattern of cancer
involved in metronomic trials, data regarding drugs employed in
metronomic chemotherapy trials and to compare the outcome as
favourable, unfavourable or equivocal to between conventional
regimen versus metronomic regimen for different tumours.
This comprehensive analysis was carried by Department of
Pharmacology, Saveetha Medical College and Haasan Institute
of Medical Sciences between January and April 2016. Fifty
chemotherapy trial data were taken sequentially from web. The main
sources were official website of Clinical Trial Forum, USA and Clinical
Trial Registry India (CTRI). Evidence on efficacy and safety of such
metronomic chemotherapy trials was gathered from various data
published in Medline, New England Journal of Medicine (NEJM),
Lancet Oncology and other journals with high credentials.
Regimen considered as favourable when there is increase in survival
rate, reduction in surrogate markers or less number of adverse
events. Results quoted as unfavourable where cancer trial registry
data showed neither reduction morbidity and mortality or reduction in
surrogate marker. Increased number of adverse events if mentioned
in metronomic regimen is also considered as unfavourable. Results
quoted as unequivocal when there is no significant difference
between conventional and metronomic regimen in terms of efficacy
or safety profile. Descriptive statistics and non-parametric tests
were applied to infer the findings.
results Of the lIterAture seArch
As detailed out in [Table/Fig-1], breast -15(30%), colon- 5(10%)
ovarian -5(10%), prostate-5(10%) and others including haematologic,
soft tissue and nervous system malignancies -20 (50%). Totally 18
drugs were used as single drug and in combinations in 50 trials.
They were cyclophosphamide –27 methotrexate – 10, capecitabine
– 9 celecoxib – 7 bevacizumab – 4 vinorelbine – 7, etoposide –
5, dacarbazine – 1, docetaxel – 3, temozolamide – 3, cisplatin –
3, gemcitabine – 2, sirolimus – 2, doxorubicin – 1, paclitaxel – 1,
irinotecan – 1, sorafenib, tegafur/uracil – 1.
Pharmacology Section
Metronomic Chemotherapy:
Seems Prowess to Battle against
Cancer in Current Scenario
Prema muthuSamy
1, KriShnan VengadaragaVa Chary
2, gK nalini
3Keywords:
Cancer resistance, Low dose chemotherapy, Maintenance chemotherapy
ABst
rAc
t
Introduction:
Metronomic chemotherapy is an emerging
method of chemotherapy. Metronomic ’lowdose’ chemotherapy
regimen induces tumour dormancy and reduces cancer
resistance against anticancer drugs. It tends to improve overall
success rate of cancer chemotherapy than conventional cyclical
regimen.
Aim:
The aim of this systemic review was to provide
comprehensive data of metronomic chemotherapy trials,
regimens used and it’s outcome in cancer therapeutics.
Materials and Methods:
Fifty chemotherapy trial data were
searched sequentially from web. The main sources were official
website of Clinical trial forum, USA and Clinical Trial Registry
India (CTRI). Evidence on efficacy and safety of such metronomic
chemotherapy trials was gathered from various data published
in Medline, New England Journal of Medicine (NEJM), Lancet
Oncology and other journals with high credentials. As a result
of our search, out of 50 trials including breast -15(30%), colon-,
5(10%) ovarian -5(10%), prostate-5(10%) and others including
haematologic, soft tissue and nervous system malignancies -20
(50%). Twenty seven trials showed favourable, 20 trials showed
equivocal outcome and 3 trials reported unfavourable outcome.
Overall comparison showed definitive statistical significance for
using metronomic regimen (p-0.05).
S. no. Cancer trial name author’s name drug given end point Outcome 1 Metronomic cyclophosphamide and capecitabine
combined with bevacizumab in advanced breast cancer
Silvia Dellapasqua,
et al.,
Cyclophosphamide and capecitabine Bevacizumab
Response rate Favourable
2 Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with her-2 positive metastatic breast cancer
Laura Orlando et
al.,
Trastuzumab Cyclophosphamide and
methotrexate
Progression free survival Favourable
3 Zd6474 (zactima) and metronomic chemotherapy in
advanced breast cancer Erica Mayer et al., cyclophosphamide Vandetanib methotrexate
Progression free survival Favourable
4 Prolonged clinical benefit with metronomic chemotherapy in patients with metastatic breast cancer
Orlando L et al.,
Cyclophosphamide (ctx) and methotrexate (mtx) (cm)
Determine the safety and tolerability of combination
therapy
Favourable
5 Safety and therapeutic effect of metronomic chemotherapy with cyclophosphamide and celecoxib in advanced breast cancer patients
Perroud HA et al.,
Cyclophosphamide and celecoxib
Progression free survival Favourable
6 Continuous low-dose oral chemotherapy in recurrent and persistent carcinoma of cervix following chemoradiation: A comparative study between prolonged oral cyclophosphamide and oral etoposide
Upasana Baruah et
al.,
Oral cyclophosphamide and
oral etoposide Progression free survival Favourable
7 Cyclophosphamide, methotrexate metronomic chemotherapy for the palliative treatment of breast cancer. A comparative pharmacoeconomic evaluation
Bocci G et al.,
Cyclophosphamide, methotrexate
Response rate Favourable
8 Capecitabine metronomic chemotherapy plus aromatase inhibitor for postmenopausal hormone receptor positive breast cancer
Guang-yu Liu et al.,
Capecitabine Letrozole Cost saving/ cost effective Favourable
9 Low-dose metronomic oral administration of vinorelbine in the first-line treatment of elderly patients with metastatic breast cancer
Addeo R
et al., Vinorelbine Adverse events Progression free survival Favourable
10 Efficacy of capecitabine metronomic chemotherapy to triple-negative breast cancer (sysucc-001)
Yuan Zhong-yu et al.,
Capecitabine Progression-free survival Equivocal
11 Vinorelbine metronomic pluslapatinib for
overexpressing her-2 metastatic breast cancer Mavrudis Dimitris et al.,
Vinorelbine lapatinib Disease-free survival Equivocal
12 Low-dose/metronomic (ldm) chemotherapy for metastatic breast cancer
Cyclophosphamide, capecitabine, methotrexate,
celecoxib, pamidronate
Overall response rate Equivocal
13 Low dose chemotherapy with aspirin in patients with
breast cancer after neoadjuvant chemotherapy Chamberlin Mary et al.,
Cyclophosphamide and
methotrexate and aspirin Rate of response (rr) + rate of stable disease (sd) Equivocal
14 Maintenance metronomic chemotherapy for
metastatic colorectal carcinoma David L et al., Capecitabine, celecoxib and methotrexate Toxicity and safety Biomarker analysis Equivocal
15 Low dose metronomic poly-chemotherapy for
metastatic crc (ldmchemocrc) Ofer Purim et al., cyclophosphamide Capecitabine methotrexate celecoxib
Length of progression free
survival (pfs) Equivocal
16 Metronomic therapy in patients with metastatic melanoma
Marc S. Ernstoff et
al.,
Vinblastine cyclophosphamide
dacarbazine
The median progression free survival
Equivocal
17 Study of combination of metronomic oral vinorelbine and sorafenib in patients with advanced non-small cell lung cancer
Eng-Huat Tan et al.,
Oral vinorelbine sorafenib Progression free survival Equivocal
18 Metronomic oral vinorelbine in advanced breast
cancer and non small cell lung cancer Cazzaniga ME et al., Vinorelbine Response rate Favourable 19 Metronomic oral vinorelbine in patients with
metastatic tumours
Evangelos Briasoulis
et al.,
Vinorelbine Response rate Favourable
20 Efficacy, safety, and potential biomarkers of thalidomide plus metronomic chemotherapy for advanced hepatocellular carcinoma. Open- labeled, single-arm, multicentered, investigator-initiated study
Shao YY
et al., tegafur/uracil Thalidomide Time to treatment failure Progression free survival Favourable
21 Metronomic therapy with cyclophosphamide and
dexamethasone for prostate carcinoma Glode LM et al., Cyclophosphamide Dexamethasone Response evaluation criteria in solid tumours (recist) Favourable
22 Clinical outcome of patients with docetaxel resistant hormone refractory prostate cancer with second line cyclophosphamide based metronomic chemotherapy
Nelius T et
al., Cyclophosphamide Psa Favourable
23 High-dose celecoxib and metronomic “low-dose” cyclophosphamide is an effective and safe therapy in patients with relapsed and refractory aggressive histology non–hodgkin's lymphoma Multicenter phase II prospective study
Buckstein R
et al., cyclophosphamideCelecoxib and Psa response Survival and toxicity Favourable
24 Phase II study of metronomic chemotherapy for recurrent malignant gliomas in adults
Santosh Kesari et al.,
Etoposide, cyclophosphamide plus
thalidomide Celecoxib
25 Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase ii study
Reardon DA et al.,
Etoposidebevacizumab Progression free survival Unfavourable
26 Metronomic chemotherapy enhances the efficacy of
antivascular therapy in ovarian cancer Kamat AA et al., Docetaxel Progression free survival Favourable
27 Phase II clinical trial of bevacizumab and low dose metronomic oral cyclophosphamide in recurrent ovarian cancer a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia
Garcia AA
et al., Cyclophosphamide Bevacizumab Response rate Favourable
28 Phase II trial of low dose continuous (metronomic) treatment of temozolomide for recurrent glioblastoma
Kong DS
et al., Temozolomide Progression free survival Favourable
29 Metronomic capecitabine and docetaxel as second-line chemotherapy for advanced gastric cancer(MICADO)
Vincenzo Catalano et al.,
Capecitabine Docetaxel Progression free survival Equivocal
30 Protracted etoposideduring induction therapy for high risk neuroblastoma (PEPI)
Peter Zage et al.,
Protracted oral etoposide adriamycin and cyclophosphamide iv
cisplatin and iv bolus etoposide
Tumour response Equivocal
31 Combining low-dose or metronomic chemotherapy
with anticancer vaccines Stephen R et al., gemcitabine, doxorubicinCyclophosphamide, Response rate Equivocal
32 Effect of maximum-tolerated doses and low-dose metronomic chemotherapy on serum vascular endothelial growth factor and thrombospondin-1 levels in patients with advanced nonsmall cell lung cancer
Tas F et al., Cisplatin Docetaxel Response rate Unfavourable
33 Cyclophosphamide "metronomic" chemotherapy for palliative treatment of a young patient with advanced epithelial ovarian cancer
Samaritani R et al.,
Cyclophosphamide Decrease in biomarker levels Favourable
34 Metronomic therapy concepts in the management of adrenocortical carcinoma
Berruti A et al.,
Gemcitabine and fluoropyrimidines
Progression-free survival time Favourable
35 Metronomic oral vinorelbine as first-line treatment in elderly patients with advanced non-small cell lung cancer: results of a phase ii trial (move trial)
Camerini A et al.,
Oral vinorelbine Response rate Equivocal
36 Metronomic chemotherapy in patients with advanced solid tumour with bone metastasis and advanced pretreated osteosarcoma
Maud et al., Sirolimus combined with cyclophosphamide
methotrexate and zoledronate
Overall response rate (ORR),
clinical benefit Equivocal
37 A pilot study of a metronomic chemotherapy regimen with weekly low-dose docetaxel for previously treated non-small cell lung cancer
Takashi
Yokoi et al., Docetaxel Response rate Favourable
38 Maintenance bevacizumab only or bevacizumab plus metronomic chemotherapy in advanced colorectal cancer
Alberto Z
et al., Bevacizumab Capecitabine Cyclophosphamide Objective response rate, disease control rate Equivocal
39 Sirolimus in combination with metronomic chemotherapy in children with recurrent and/or refractory solid and CNS tumours
Thomas et al.,
Sirolimus celecoxib etoposide cyclophosphamide
Progression-free survival Equivocal
40 A pilot study of metronomic temozolomide treatment in patients with recurrent temozolomide-refractory glioblastoma
Kong DS
et al., Temozolamide response to treatment for Change in radiographic solid tumours
Equivocal
41 Antiangiogenic effect of metronomic paclitaxel treatment in prostate cancer and non-tumour tissue in the same animals: a quantitative study
Lennernäs B et al.,
Paclitaxel Progression-free survival Favourable
42 Oral metronomic cyclophosphamide in elderly with metastatic melanoma
Borne E et al.,
Cyclophosphamide Safety Objective response rate and overall survival
Favourable
43 Phase ii study of metronomic chemotherapy with bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy
David A. Reardon et al.,
Etoposide Temozolomide Progression-free survival Unfavourable
44 Capecitabine “metronomic” chemotherapy for palliative treatment of elderly patients with advanced gastric cancer after fluoropyrimidine-based chemotherapy
Shen J et al., Capecitabine Progression-free survival Favourable
45 Low dose metronomic oral cyclophosphamide for hormone resistant prostate cancer: a phase II study
Lord R et al., Cyclophosphamide Safety and toxicity Favourable
46 Metronomic therapy for pediatric patients with solid tumours at high risk of recurrence
Ted Zwerdling
et al.,
Bevacizumab cyclophosphamide valproic
acid temsirolimus
5 year event free survival Equivocal
47 Safety and efficacy of metronomic
cyclophosphamide, metformin and olaparib in endometrial cancer patients (endola)
Benoit et al., Olaparib metformin metronomic cyclophosphamide
Progression free survival Equivocal
48 A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients
G Allegrini
et al., Irinotecan PK/PD profile Favourable
49 Metronomic chemotherapy: possible clinical application in advanced hepatocellular carcinoma
Torimura T et al.,
Cyclophosphamide Flurouracil
50 Low-dose metronomic chemotherapy with cisplatin: can it suppress angiogenesis in hepatocarcinoma cells
Fang-Zhen Shen et al.,
Cisplatin Safety and efficacy Equivocal
As evident from above, cyclophosphaomide and methotrexate were
used most often in many tumours and doss employed was 50mg
once daily and 2.5mg twice daily respectively. A total of 27 trials
showed favourable 20 trials showed equivocal outcome and three
trials reported unfavourable outcome. Overall comparison showed
definitive statistical significance for using metronomic regimen
(p-0.05).
Detailed results of 50 trials with type of cancer, drugs used end
points observed by investigator and outcome is depicted in [Table/
Fig-1].
dIscussIOn
Our study was undertaken to analyse and provide comprehensive
data of newer metronomic chemotherapy regimen which showed
convincing results in various experimental studies and paved to begin
cancer trials with metronomic regimen. In our study most commonly
employed drugs were alkylating agent, cyclophosphamide and
anti-metabolite methotrexate. Our analysis showed breast cancer were
commonly employed with metronomic regimen probably due to
its more common occurrence and metronomic regiment is highly
favolurable in breast cancer. Success of metronomic regimen quoted
by us was supported by systematic review of Banys-Paluchowski M
et al., among European nations; however the drug employed was
capeciabine which is different from our analysis [3].
Colon cancer, prostate cancer and ovarian cancers using
metronomic regimen showing favourable outcome in their endpoints.
These findings are well supported by similar analysis conducted by
investigators worldwide [6-8].
In case of three trials of small cell cancer of lung, metronomic
regimen did not produce any additional benefits. The postulated
reason was, in cases of small cell or non-small cell lung cancer
metronomic drug and dosage regimen is yet to be refined when
compared to other protocols used in various malignancies. Elharrar
X et al., have discussed the aforesaid reason elaborately the failure
of designing successful regimen in lung cancer in his publication
BMC cancer 2016 [9].
Glioblastoma and other nervous system tumours including
neuroblastoma did not show convincing benefits in either of the
regimen. These tumours are aggressive and carries poor prognosis
in general remains unaltered by metronomic regimen [10].
Mechanisms involved in administering low dose metronomic
regimen than maximum tolerated dose used in regular or cyclical
chemotherapy regimen is now adequately elucidated. The
mechanisms are low dose daily administration of drugs which
reduces cancer drug resistance and induces tumour dormancy.
Metronomic regimen reduces interleukins and metallopeoteinases,
‘switch off’ Vascular Endothelial Growth Factor (VEGF) genes
responsible for angiogenesis and hence, metastasis in cancer
growth [11,12].
Changing the conventional regimen to metronomic regimen is termed
as “chemoswitch” by oncologists and hailed by many. Metronomic
regimen are not devoid of adverse effects, shared toxicities of anti-
cancer drugs like nausea, vomiting, alopecia are applicable but they
are expected and shown to be less in many trials [13,14].
future dIrectIOns
Metronomic regimen with conventional regimens is showing
evidenced based information to support their use [15,16]. Future
directions should include using newer biologics in metronomic
regimen to improve its efficiency with conventional drugs. Cancer
therapeutic committee should frame a common metronomic
regimen which will be used as reference module in many developed
nations. Common consensus if arrived on metronomic regimen,
it will help to policy decision in monetary benefits and resource
allocation at institutional to national level. As many of the cancer
drugs has propensity to induce second tumour effect, long term
administration of metronomic regimen should be guarded with the
risk involved. Pooling of many meta-analysis outcome from trials
conducted from various ethnicities is a need to see any variation in
response.
Our analysis provides the preliminary success trend of metronomic
regimen versus cyclical chemotherapy trial and hence, systematic
review of a particular malignancy was not mentioned as each of it
has to be with meticulous inclusion and exclusion of various cancer
using metronomic regimen.
cOnclusIOn
Metronomic regimens often employ cyclophosphamide (50mg/d) and
methotrexate (5mg/d) to treat various malignancies and convincingly
effective in many cases. Breast, colon, ovarian and prostate cancer
have shown favourable outcome with metronomic regimen whereas
small cell lung cancer and nervous system malignancies are not
yielding any additional benefits with metronomic regimen.
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PartiCularS OF COntriButOrS:
1. Postgraduate, Department of Pharmacology, Haasan Institute of Medical Sciences, Haasan, Karanataka, India. 2. Assistant Professor, Department of Pharmacology, Saveetha Medical College, Chennai, Tamil Nadu, India. 3. Professor, Department of Pharmacology, Haasan Institute of Medical Sciences, Haasan, Karanataka, India.
name, addreSS, e-mail id OF the COrreSPOnding authOr: Dr. Krishnan Vengadaragava Chary,
1B, Blude Diamond Apartment, Mothilal Street, T Nagar, Chennai -17, Chennai, Tamil Nadu, India. E-mail: [email protected]
FinanCial Or Other COmPeting intereStS: None.
Date of Submission: aug 27, 2016 Date of Peer Review: Sep 08, 2016 Date of Acceptance: Sep 23, 2016 Date of Publishing: nov 01, 2016
Maiti R. Metronomic chemotherapy.
